There is substantial evidence that the Western-style diet, rich in fats and calories, is a critical factor in the development of obesity and other chronic diseases, including cancer. Although the underlying mechanisms are likely multi-faceted, inflammation certainly plays an important role in High Fat Diet-induced obesity and cancer. Infiltrating inflammatory cells as well as systemic and local levels of pro-inflammatory mediators provide in ideal micro-milieu for tumor development Anti-inflammatory strategies have been shown in many animal models to delay or prevent the development of cancers and are widely considered intriguing approaches for cancer prevention. Our preliminary studies have shown that a high fat, high calorie diet (HFCD) in the presence of an inflammatory micro-environment substantially accelerates the development and progression of pancreatic cancer precursor lesions in a genetically engineered animal model of pancreatic cancer development Furthermore, our previous published studies have demonstrated that oral administration of an anti-inflammatory drug delays the progression of pancreatic cancer precursor lesions in the conditional Kras mouse model of pancreatic cancer development. In addition, dietary supplementation of fish oil inhibited pancreatic cancer grov\rth in a xenograft mouse model, which was accompanied by reduced levels of pro-inflammatory prostaglandin species. The overarching hypothesis of this Project is that a HFCD promotes pancreatic cancer development and growth. This effect mediated and accelerated by the presence of an inflammatory micro-environment. Targeting the inflammatory response may prevent pancreatic cancer development promoted by the HFCD. To test our hypothesis the following three Specific Aims are proposed. 1) To determine the importance of pancreatic inflammation in HFCD-induced pancreatic cancer development, 2) to characterize the importance of eicosanoids in HFCD-induced pancreatic cancer development and investigate their mechanisms, and 3) to determine the efficacy of fish oil as an anti- inflammatory strategy to reduce pancreatic cancer development. State-of-the-art genetically engineered animal models will be utilized to test the hypotheses. Underlying mechanisms will be dissected in cell culture systems that mimic the different stages of pancreatic cancer development. RELEVANCE (See instructions): We anticipate proving our hypothesis that strategies aimed at inhibiting the inflammatory component, e.g. through fish oil, significantly delay or prevent the tumor-promoting effects of the high fat, high calohe diet. Since today fish oil is widely used as a general health-promoting dietary supplement, our studies will provide the scientific rationale for the use of fish oil to prevent pancreatic cancer and elucidate its mechanism. Our results may also be transferable to other obesity-related cancer and even non-malignant chronic diseases.